INDEX toxicology

Workers in the metals treatment industry are exposed to fumes, dusts, and mists containing metals and metal compounds, as well as to various chemicals from sources such as grinding wheels and lubricants. Exposure can be by inhalation, ingestion, or skin contact. Historically, metal toxicology was concerned with overt effects such as abdominal coHc from lead toxicity. Because of the occupational health and safety standards of the 1990s such effects are rare. Subtie, chronic, or long-term effects of metals treatment exposure are under study. An index to safety precautions for various metal treatment processes is available (6). As additional information is gained, standards are adjusted. 

The absorption, distribution, and accumulation of lead in the human body may be represented by a three-part model (6). The first part consists of red blood cells, which move the lead to the other two parts, soft tissue and bone. The blood cells and soft tissue, represented by the liver and kidney, constitute the mobile part of the lead body burden, which can fluctuate depending on the length of exposure to the pollutant. Lead accumulation over a long period of time occurs in the bones, which store up to 95% of the total body burden. However, the lead in soft tissue represents a potentially greater toxicological hazard and is the more important component of the lead body burden. Lead measured in the urine has been found to be a good index of the amount of mobile lead in the body. The majority of lead is eliminated from the body in the urine and feces, with smaller amounts removed by sweat, hair, and nails. 

If tlie pollutant causes iui acute non carcinogenic risk, tlie inaximuin one hour concentration is used for C, and tlie acute reference exposure limit is used for tlie REL. Likewise, if tlie pollutant causes a clironic non carcinogenic risk, tlie one year average concentration is used, as is tlie clironic reference exposure limit. In tliis procedure, a Iiazard index is calculated for each pollutant separately, and tlien tlie indices are summed for each toxicological endpoint (i.e., tlie respiratory system, tlie central nervous system, etc.). Finally, tlie total hazard index is tlien compared to a value wliich is considered significant. 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

As is needed for all potential risks for chemical substances, an index of toxicity enables quantification of risk. Nevertheless, it only applies to risk by inhalation, which is yet the most common as well as insidious risk under normal working conditions with chemical substances. However, this approach should be treated with caution because of the difficulties inherent in toxicological risks. At this stage of the analysis it is essential to work in collaboration with the company doctor, whose total agreement is necessary. 

Boriani E, Mariani A, Badema D, Moretti C, Lodi M, Benfenati E (2010) ERICA a multiparametric toxicological risk index for the assessment of environmental healthiness. Environ Int 36 665-674... 

Department of Health and Human Services. National Toxicology Program, Technical Reports. August 9, 2005. http //ntp.niehs.nih.gov/index.cfm objectid=070E4598-9C8B-DF77-lC266EBE08732EB4. March 22,2006. 

Bondy SC, Komulainen H. 1988. Intracellular calcium as an index of neurotoxic damage. Toxicology 49(l) 35-41. 

Direct isolation of sufficient quantities of each metabolite for structural characterization, assay validation and pharmacological or toxicological testing from in vivo studies using biological specimens is, therefore, often impossible, particularly from dmgs with a low therapeutic index. Furthermore, many metabolites have structural modifications which are difficult to replicate by traditional chemical methods. A number of synthetic steps may be required to prepare such metabolites from the API, or, in the worst case, a completely new synthetic route may need to be developed. 

Toxicologic research (Chapter 8) on the effects of ozone in laboratory animals has demonstrated that exposure to airborne ozone at less than 1 ppm for a few hours produces numerous changes in cell and organ structure and function. The lowest concentrations that produce these changes differ somewhat among different species of laboratory animals and with the effect under observation. However, several functional and morphologic indexes of response to ozone are altered with exposures to concentrations of about 0.2-0.5 ppm over periods ranging from a few minutes to several weeks. 

ECETOC. 2007b. European Centre for Ecotoxicology and Toxicology of Chemicals (publications) website http /www.ecetoc.org/Content/Default.asp PagelD = 21 ECVAM. 2007. European Center for Validation of Alternative Methods website. http /ecvam.jrc.it/index.htm EU. 2006. The DG Environment REACH website. http /ec.europa.eu/environment/chemicals/reach EU. 2007. European Commision, Research Science and Society website The role of ethics in EU research. 

There are no specific guidance criteria available for the selection of the index compound. US-EPA (1986) has suggested that the index compound should be the member of the group that is the best studied and has the largest body of scientific data of acceptable quality. This will be associated with a low AF and lead to the lowest combined risk. However, this has been criticized for using data on well-studied compounds to improve the acceptability of compounds that have poor toxicological databases. 

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